Hypoxia in Radiotherapy

Hypoxia has been strongly associated with local failure in NSCLC tumors and is an indicator of poor prognosis.

Hypoxia in tumors is a pathophysiologic feature of microcirculatory dysfunction, as well as poor oxygen diffusion, and is strongly associated with tumor proliferation, malignant progression, and resistance to therapy. Tumor cells are uniquely capable of adaptation to hypoxic microenvironments through the expression of angiogenic factors, glycolytic enzymes, and stress proteins. The hypoxic adaptation of tumor cells is primarily regulated at the transcriptional level through hypoxia-inducible factor-1 (HIF-1), which is capable of up-regulating more than 400 genes, including pro-angiogenic factors, such as vascular endothelial growth factor (VEGF). Recent advances in molecular biology have revealed a role for a subset of ribonucleic acids (RNAs) in regulating specific genes. micro-RNAs, as they are known, have been shown to play a role in regulating gene expression under normal and disease conditions. In particular, recent studies have demonstrated a role for micro-RNAs in regulating the expression of HIFs.

For optimization of radiotherapy it would be desirable to have a non-invasive method for localization of hypoxic cell sub-populations within the tumor. Such localization would permit the delivery of significantly higher radiation doses to the hypoxic cell sub-population and improve tumor control. For most cancer treatment centres the available non-invasive technique for imaging tumor metabolism in a clinical setting is Positron Emission Tomography (PET) with the tracer fluoro-deoxyglucose (FDG). High FDG uptake is characteristic of malignant tumors, particularly of aggressive tumors with high metastatic potential.

The FDG signal is indicative of the up-regulation of glycolytic metabolic pathways and is believed to have resulted from selective pressure in pre-malignant cells, which were able to withstand hypoxia by switching to anaerobic glycolysis. A major consequence of HIF-1a activation is the stimulation of glycolysis through increased transcription of glycolytic genes. In cancer cells HIF-1 can be reversibly increased by physiological stress (i.e. hypoxia) and constitutively activated under normoxic conditions as a result of heritable alterations. In either case the result is increased expression of glycolytic proteins, which could be detected in PET image.